tbuckley/cabot-search huggingface dataset:
Real-world time on treatment analysis of pembrolizumab treated recurrent/metastatic head &amp; neck squamous cell carcinoma (R/M HNSCC) patients stratified by ECOG PS in the United States.
Authors: Christopher Matthew Black, Liya Wang, Karthik Ramakrishnan, Vladimir Turzhitsky
Journal: Journal of Clinical Oncology (2022)

e18007 Background: There is limited evidence on the real-world use of pembrolizumab therapy post-approval in 1L R/M HNSCC. The study estimated real-world time on treatment (rwToT) of pembrolizumab monotherapy and pembrolizumab + platinum + 5FU for 1L R/M HNSCC patients, stratified by ECOG PS. Methods: This retrospective study of the nationwide de-identified electronic health record (EHR)-derived Flatiron Health Advanced H&amp;N database selected patients initiating pembrolizumab monotherapy or pembrolizumab + platinum + 5FU between 07/01/19 - 12/31/20 with follow-up until 07/31/21. Patients with prior platinum-based therapy ≤6 months, prior primary cancers, or treatment with a clinical study drug were excluded. rwToT was defined as length of time between first and last documented administration date pembrolizumab. Patients with a record of next line of therapy, death, or treatment gap ≥120 days from the last administration date were considered discontinued. Patients without a discontinuation event were censored at the end of follow up. Kaplan-Meier analysis was conducted to assess median rwToT and landmark on-treatment rates. All results were stratified by ECOG PS 0-1 (similar to KEYNOTE-048, the registrational clinical trial) and ECOG PS 2-3. Results: A total of 402 patients initiated 1L treatment with pembrolizumab therapy. Of those patients, 297 (73.9%) had a recorded ECOG PS score, majority with an ECOG PS score of 0/1 (Overall: 77.8%, pembrolizumab monotherapy: 70.5%, pembrolizumab + platinum + 5-FU: 84.1%). The median rwToT was higher among the ECOG 0/1 patients compared to ECOG 2/3 patients for both regimens (pembrolizumab monotherapy: 4.4 vs 2.2 months, pembrolizumab + platinum + 5-FU: 5.0 vs 3.5 months). Conclusions: In the real-world, treatment duration with pembrolizumab monotherapy or pembrolizumab+platinum+5-FU in 1L R/M HNSCC was similar to KEYNOTE-048, when restricted to a trial-matched population of ECOG PS 0-1 patients. Treatment duration tended to be shorter in the real-world ECOG PS 2/3 population, who are commonly excluded from clinical trials.[Table: see text]
MEDB-87. Transcriptome-driven drug repurposing in group 3 medulloblastoma
Authors: David Doss, Ranjana Kanchan, Naveenkumar Perumal, Surinder Batra, Sidharth Mahapatra
Journal: Neuro-Oncology (2022)

Abstract Across the molecular spectrum of medulloblastoma (MB), group 3 (G3) tumors are the most aggressive with &amp;lt;50% five-year survival, the lowest of all MB subgroups. G3 MB tumors are characterized by frequent metastases at diagnosis, unique methylation profiles, MYC amplification, and i17q, but these unique molecular features have yet to be exploited for therapeutic purposes despite their contribution to the disease process. As such, we sought to address this gap in survivorship by identifying FDA-approved compounds with the potential to inhibit cellular processes critical to G3 MB tumor proliferation and metastasis, aiming to exploit the unique molecular pathogenesis of G3 tumors. Guided by analysis of RNA-sequencing data from locally obtained, patient-derived MB samples against the LINCS chemical perturbagens database, we identified nortriptyline (NT), a tricyclic antidepressant, as a candidate MB therapeutic due to: 1) its ability to revert the transcriptomic signature of G3 MB to a normal cerebellum-like state and 2) its ability to cross the blood-brain barrier. We first identified the IC50 of NT in D425 and HDMB03 cells as 28μM and 20μM, respectively. Then, we observed that NT increased apoptosis of HDMB03 cells 3-fold by flow cytometry and confirmed our observations with Western blotting of apoptotic markers. Additionally, NT treatment resulted in abrogation of colony formation, impairment of wound healing, and inhibition of cell migration and invasion in vitro in HDMB03 cells. In all, transcriptome-driven drug repurposing holds great promise, as identifying novel uses for compounds with a known safety profile can deliver effective treatments into the hands of both patients and physicians in an expedited manner when compared to traditional means.
Prospective two-arm study of fertility in men with COVID-19
Authors: D. Enikeev, M. Taratkin, A.O. Morozov, V. Petov, D. Korolev, A. Shpikina, L. Spivak, S. Kharlamova, I. Shchedrina, O. Mestnikov, D. Fiev, T. Ganzha, M. Geladze, A. Mambetova, E. Kogan, N. Zharkov, G. Demyashkin, S. Shahrokh, P. Glybochko
Journal: European Urology (2022)
Using a standard implementation science framework to improve clinical trial enrollment for a community Tennessee oncology center.
Authors: Neha M Jain, Philip Edward Lammers, Michael R. Savona, Travis John Osterman, Salil Goorha
Journal: Journal of Clinical Oncology (2022)

e18586 Background: Recommendations for clinical trial consideration are ubiquitous across all cancers. However, it is challenging to identify patients from underrepresented communities and offer them opportunities to enroll in clinical trials due to a multitude of reasons including social determinants of care, distance from clinical resources, lack of resources, etc. As part of the Leukemia &amp; Lymphoma Society (LLS) Influential Medicine Providing Access to Clinical Trials (IMPACT) study, Vanderbilt-Ingram Cancer Center (Nashville, TN) partnered with Baptist Cancer Center (BCC, Memphis, TN) to improve accrual of trials for patients with Hodgkins lymphoma. BCC has an active NCI Community Oncology Research Program (NCORP) grant with 12 affiliated sites spread across Arkansas, Tennessee, and Mississippi and provides care for underrepresented minority, and underserved communities. Methods: We chose the Consolidated Framework for Implementation Research (CFIR), as a conceptual model to guide assessment of the existing process and inherent opportunities. We created a secure REDCap survey to identify timepoints in the existing clinician workflow and research sites that provide the best opportunities to discuss clinical trials with the patient. Retrospective data was collected for 67 patients diagnosed with Hodgkins lymphoma, who received care at six sites affiliated with BCC. A manual chart review was performed to extract data from the electronic medical record. Results: We observed that 73% of the patients from 2 sites already had an established diagnosis of Hodgkins lymphoma at the time of referral to the medical oncologist. By contrast, only 33% of patients from the remaining 4 sites had an established diagnosis at the time of referral. In these cases, the diagnosis was established after pathological testing ordered by the oncologist was performed. Conclusions: Using our analysis, we identified 2 sites from a large healthcare network that would benefit greatest from implementing pre-screening for clinical trials before the first visit with a medical oncologist. Further, we determined that efforts/resources for trial screening at the remaining 4 sites would be best served after pathological evidence of disease was established. Clinical trial enrolment is a multi-step process and needs substantial human and financial resources. Implementation science interventions can help to guide judicious use of resources while improving patient care in rural and underserved communities.[Table: see text]
α Cell dysfunction in islets from nondiabetic, glutamic acid decarboxylase autoantibody–positive individuals
Authors: Nicolai M. Doliba, Andrea V. Rozo, Jeffrey Roman, Wei Qin, Daniel Traum, Long Gao, Jinping Liu, Elisabetta Manduchi, Chengyang Liu, Maria L. Golson, Golnaz Vahedi, Ali Naji, Franz M. Matschinsky, Mark A. Atkinson, Alvin C. Powers, Marcela Brissova, Klaus H. Kaestner, Doris A. Stoffers
Journal: Journal of Clinical Investigation (2022)

BACKGROUNDMultiple islet autoantibodies (AAbs) predict the development of type 1 diabetes (T1D) and hyperglycemia within 10 years. By contrast, T1D develops in only approximately 15% of individuals who are positive for single AAbs (generally against glutamic acid decarboxylase [GADA]); hence, the single GADA+ state may represent an early stage of T1D.METHODSHere, we functionally, histologically, and molecularly phenotyped human islets from nondiabetic GADA+ and T1D donors.RESULTSSimilar to the few remaining β cells in the T1D islets, GADA+ donor islets demonstrated a preserved insulin secretory response. By contrast, α cell glucagon secretion was dysregulated in both GADA+ and T1D islets, with impaired glucose suppression of glucagon secretion. Single-cell RNA-Seq of GADA+ α cells revealed distinct abnormalities in glycolysis and oxidative phosphorylation pathways and a marked downregulation of cAMP-dependent protein kinase inhibitor β (PKIB), providing a molecular basis for the loss of glucose suppression and the increased effect of 3-isobutyl-1-methylxanthine (IBMX) observed in GADA+ donor islets.CONCLUSIONWe found that α cell dysfunction was present during the early stages of islet autoimmunity at a time when β cell mass was still normal, raising important questions about the role of early α cell dysfunction in the progression of T1D.FUNDINGThis work was supported by grants from the NIH (3UC4DK112217-01S1, U01DK123594-02, UC4DK112217, UC4DK112232, U01DK123716, and P30 DK019525) and the Vanderbilt Diabetes Research and Training Center (DK20593).
Tracking changes in circulating stromal cells and circulating tumor cells predicts responsiveness of new line induction in metastatic breast cancer after 1 cycle of therapy.
Authors: Daniel L Adams, R. Katherine Alpaugh, Rena G. Lapidus, Saranya Chumsri, Carolina Reduzzi, Cha-Mei Tang, William Williams, Massimo Cristofanilli
Journal: Journal of Clinical Oncology (2022)

3056 Background: In metastatic Breast Cancer (mBC), Circulating Tumor Cells (CTCs) are established prognostic indicators of patients (pts) not responding to new lines of therapy and who have poor clinical outcomes. However, CTCs are typically found in &lt; 20% of mBC pts and many pts without CTCs will also progress. Recently an inflammatory pro-tumorigenic macrophage emanating from tumor stroma (i.e. Cancer associated macrophage-like cell [CAML]) was found in &gt; 90% of mBC pts and were also indicative of poor clinical outcomes. As CTCs &amp; CAMLs are isolated in conjunction from a single blood sample, and both are prognostic for therapy response, we evaluated CTCs &amp; CAMLs before and after initiation of new therapies in mBC to determine their combined prognostic/predictive values. Methods: An observational prospective 2-year multi-institutional study was undertaken to evaluate CTCs &amp; CAMLs before, and after, induction of any new line of therapy in pts with diagnosed mBC (n = 101). Anonymized and blinded blood samples were taken at baseline (BL), prior to starting a new systemic therapy, and a 2nd sample (T1) taken after therapy initiation (̃30 days). Blood was filtered by CellSieve filtration. The quantities and subtypes of CTCs &amp; CAMLs were analyzed based on RECIST v1.1 for progression-free survival (PFS) and overall survival (OS) hazard ratios (HRs) by censored univariate &amp; multivariate analysis at 2 years. Results: CTCs were identified in 35% (n = 35/101) of pts at BL &amp; 24% (n = 24/101) at T1, with a single CTC at T1 being highly prognostic for worse PFS HR = 6.2 95%CI 3.0-13.2, p &lt; 0.001 &amp; OS (HR = 5.1 95%CI 2.0-13.4, p = 0.002. In parallel, CAMLs were found in 93% of BL and 86% of T1 samples, and whose decreases were significantly prognostic for improved PFS (HR = 2.7, 95%CI 1.4-5.1, p = 0.006) and OS (HR = 4.4 95%CI 1.5-13.2, p = 0.018) when CTCs were absent. Overall ≥1 CTC at T1 (n = 24) had median PFS = 2.4 &amp; mOS = 4.8 months (mos), however, in pts without CTCs plus an increase in CAMLs (n = 36) had mPFS = 5.9 &amp; mOS = 14.1 mos, while in pts without CTCs plus a decrease in CAMLs (n = 41) had mPFS = 14.8 &amp; mOS = 18.8 mos. Conclusions: Our data confirms that pts with persistent CTCs have the worst clinical outcomes. Further, simultaneous CAML quantification provided a new dynamic predictive blood based biomarker in pts without detectable CTCs which may be useful to better individualize therapy and improve outcomes, though future studies are need to validate these findings.
Characteristics and Outcomes of Hospitalized Patients in South Africa During the COVID-19 Omicron Wave
Authors: Yijia Li
Journal: JAMA (2022)

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The association of agent orange (AO) exposure with monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) progression: A population-based study.
Authors: Lawrence Liu, Mei Wang, Mark A. Schroeder, Theodore Seth Thomas, Akhil Kumar, Kristin Vargo, Feng Gao, Kristen Marie Sanfilippo, Su-Hsin Chang
Journal: Journal of Clinical Oncology (2022)

8050 Background: With limited evidence from a single center study [n=211 (11 with AO exposure)] reporting AO exposure as a risk factor for transformation, whether or not AO exposure increases the rate of transformation from MGUS to MM is unclear. Thus, we aimed to conduct a nation-wide study to determine the association between AO exposure and the risk of MGUS to MM progression. Methods: A retrospective, matched cohort study using data from the U.S. Veterans Health Administration system was conducted. Based on a power calculation, a random sample of MGUS patients with AO exposure was selected and 1:1 matched to those with MGUS without AO exposure (matching factors: age at MGUS diagnosis, race, body mass index categories). Data abstraction confirmed MGUS and MM diagnoses. In addition, information on date of diagnosis, MGUS subtype, and monoclonal protein (M-protein) values was performed. Patients were considered to have MGUS if they had M-protein detected on serum protein electrophoresis (SPEP) with immunofixation confirmation. The association of AO exposure with progression from MGUS to MM was examined using a multivariable Fine-Gray subdistribution hazard model with death as the competing event. The covariates included M-protein at MGUS diagnosis (&gt;1.5, ≤1.5 g/dL [reference]), MGUS subtype (Immunoglobulin A, light chain, and Immunoglobulin G [reference]), and Charlson comorbidity score at MGUS diagnosis. A sensitivity analysis was conducted using inverse probability treatment weighted survival analysis to evaluate the robustness of the conclusion. Results: After excluding individuals with no confirmed MGUS or M MGUS subtype, a total of 563 MGUS patients with AO exposure and 563 matched controls were included. No statistically significant difference was observed in the progression of MGUS to MM between the AO exposed group and control group (adjusted hazard ratio (aHR) 0.78, 95% confidence interval (CI) 0.53 to 1.17). The sensitivity analysis demonstrated consistent results. Conclusions: Our carefully designed study does not show an association between AO exposure and progression of MGUS to MM in a national cohort of Veterans. [Table: see text]
Multi-omics analysis reveals spatial heterogeneity of infiltrating T cells in high-grade serous ovarian cancer.
Authors: Gang Chen, Bin Yang, Xiong Li, Wei Zhang, Junpeng Fan, Chaoyang Sun
Journal: Journal of Clinical Oncology (2022)

e17603 Background: The effect of spatial immunologic variation, especially in T cell infiltration, recognition and expansion, across various tumor foci in the ovary (primary) and distant metastatic foci in the peritoneal cavity and their contribution to the limited response to immune therapy in High-Grade Serous Ovarian Cancer(HGSOC) remains unexplored. We aim to provide a detailed analysis of the landscape of heterogeneity of infiltrating T cells in primary and metastatic lesions and their differential characteristics in HGSOC. Methods: We performed multi-site sampling and simultaneous RNA sequencing (RNA-seq), whole-genome sequencing (WGS) and bulk T cell receptor (TCR) sequencing as well as single cell RNA sequencing (scRNA-seq) and paired TCR sequencing (scTCR-seq) in 9 patients (48 sites, including 19 ovarian, 11 omental, 18 other metastasis lesions) with untreated primary HGSOC. Validation by IHC, flow cytometry, another scRNA-seq data from 7 patients (32 sites, including 9 ovarian, 6 omental, 6 ascites and 11 other metastasis lesions) and spatial transcriptomics. Results: CD8 exhausted clusters that are enriched in ovarian tumors exhibited high exhaustion, tumor-specific score and low bystander score, whereas CD8 transition and NK-like clusters that are enriched in omental tumors exhibited the opposite characteristics, which was confirmed by flow cytometry. Of note, the exhausted CD8 + T cells exhibited GZMB, PRF1, FASLG and IFNG effector genes despite the expression of exhaustion markers, developing from an early differentiation state with high proliferative capacity and the process preferentially occurs in primary ovarian sites. Besides, T cells corresponding to the selected TCRs that had the same distribution as neoantigens were enriched in ovarian lesions, while the virus-specific TCR preferentially enriched in omentum samples. The association of TMB, HRD score, and COSMIC mutational signatures with antigen-engaged T cell subsets was not observed at the site level within individual patients. STARTRAC-migration analysis showed that T cell clusters in blood or other sites migrating to ovarian was extremely low or vice versa. The expression of MHC-I processing and presentation genes and MHC-I protein were higher in omental lesions, along with T cells were preferentially located in tumor region of ovarian tumors. Conclusions: We identify two different immune patterns in ovarian cancer: 1) ovarian lesions with low infiltration of mainly dysfunctional T cells and immunosuppressive Treg cells. These exhausted CD8 T cells with cytotoxic function are clonal expanded; 2) omental lesions infiltrated with non-tumor-specific bystander cells. Decreased major histocompatibility complex (MHC)-I antigen presentation ability and failure of T cell infiltration into omental tumors may contribute to lack of tumor-specific T cells in omental metastasis.
Adherence to different adjuvant endocrine therapies in HR+ HER2-breast cancer and its relation to real-world progression rates.
Authors: Ivana Durutovic, Shady Gendy, Deepa Kumar, Elise Amioka
Journal: Journal of Clinical Oncology (2022)

e12507 Background: Adjuvant hormonal therapy (Adj.) has significantly improved long-term survival of breast cancer (BC) patients with hormone receptor-positive (HR+) disease 1 . Despite proven efficacy, many breast cancer patients fail to adhere to treatment 2 . This study aims to assess patient adherence to different Adj. regimens by observing Proportion Days Covered (PDC) in relation to Real-World Data Overall Response Rate (RWD-ORR), Event Free Survival (EFS) &amp; Adverse Events Rates (AEs). Methods: ICON US Medical &amp; Prescription data was used. Analysis was limited to female BC patients who started Adj. [July’13 - June’14] &amp; further refined to HR+ &amp; HER2 negative patients by drug proxy. Patients were followed for 72 months. RWD-ORR was defined as percent of patients with no evidence of progression during follow-up. EFS was defined as time from Adj. start to first observed progression. PDC was calculated as (days on drug/duration on Adj.). AEs evaluated were endometrial &amp; bone density changes. Chi square, t-tests &amp; Fisher exact tests were used to examine Adj. regimen associations with age &amp; adherence. General linear models (GLMs) were used to examine the effect of adherence on RWD-ORRs and AEs by treatment group, adjusting for patient age at diagnosis. Results: 1,498 patients met study criteria &amp; data integrity procedures. Mean age was 60 years. Adherent patients were significantly older (57.8 vs 60.4 p &lt; 0.001). RWD-ORR was 70.4%, median EFS was not reached, median Duration on Therapy was 52 months and overall AEs was 9%; highest in leuprolide group but no statistical difference across groups. RWD-ORR was observed to be highest among the AI group. High treatment adherence (PDC 80%+) was the strongest indicator of ORR (p &lt; 0.001). RWD-ORR among those treated with AI or Tamoxifen were found to be more sensitive to adherence compared to AI/Tamoxifen. Conclusions: This study offers evidence to support provider´s messaging to patients that adherence improves outcomes when prescribing treatments. While adherence is important for positive outcomes for all regimens, some regimens appear to be more sensitive to adherence changes with respect to RWD-ORR. Further analysis including disease risk factors is needed to explain ORR - PDC relationship.[Table: see text]
Differences of quality of life between German and Dutch prostate cancer patients, who are treated with robot-assisted radical prostatectomy: Implications for international multicenter randomized controlled trials
Authors: C. Wagner, J.H. Witt, M. Kolvatzis, N. Liakos, T. Karagiotis, M. Mendrek, L. Esch, T. Jankowski, A. Schuette, S-R. Leyh-Bannurah
Journal: European Urology (2022)